The goal of this CETR center is to use a combination of innovative strategies to combat drug resistant infectious diseases. Genes that encode small molecules in bacteria have coevolved with selective environmental pressures to symbiotic hosts, such as pathways that produce protective small molecules. Taking advantage of these coevolved relationships can help guide drug discovery. This project (Project 1) will use innovative strategies to investigate the outcome of symbiosis on antimicrobial drug discovery. In particular, we will use LCMS-based untargeted metabolomics developed by us to link symbiotic natural products to niche and to drive efforts in drug discovery. To date, this approach has been highly effective, but considering the threat we now face due to drug resistant infectious diseases, a synergistic combination of expertise will be required in order to quickly identify suitable drug leads. Therefore, we will not only use metabolomics to drive discovery efforts but also combine the expertise across projects to strategically mine new sources of actinomycetes and Proteobacteria. We will take advantage of the decreasing cost of whole genome sequencing and recent advances in genomics via Project 2 to maximize our output, while utilizing the expertise of Project 3 for high content screening of interspecies interactions to stimulate growth and production of targeted bacteria. Project 1 will work closely with Core B to exploit a new paradigm in high throughput drug discovery as well as provide novel antimicrobials to Core C for in vivo evaluation. Core D will provide mechanism of action feedback, which will further drive our efforts by understanding how lead antimicrobials act. The outcome of these collaborative efforts will be suitable drug candidates to treat targeted microbial diseases.